Intergroup 0116 Trial

The well-designed INT 0116 study reported by MacDonald in 2001, established postoperative chemoradiotherapy as the standard of care for patients with resectable gastric cancer (13). Patients who underwent a complete resection with negative margins were stratified according to tumor node metastases (TNM) staging and then randomized to surgery alone (275 patients) versus surgery plus adjuvant therapy (281 patients). The treatment protocol in the adjuvant arm consisted of chemotherapy beginning 20 to 40 days after gastrectomy with 5-FU and leu-covorin for five days. Twenty-eight days after the start of chemotherapy, patients started EBRT with 45 Gy given in 180-cGy fractions five days a week for five weeks with concurrent 5-FU and leucovorin on the first four and last three days of radiation. They continued with chemotherapy 28 to 35 days after the completion of EBRT with two five-day courses of 5-FU and leucovorin one month apart (schema of INT 0116 in Fig. 1). The design of the radiation field was very strictly delineated, covering the tumor bed, proximal and distal resection margins plus 2 cm, and regional nodes as defined by the stations outlined by the Japanese Research Society for the Study of Gastric Cancer (JRSGC). The tumor bed was determined by preoperative computed tomography (CT) scans, barium studies, and surgical clips. Perigastric, celiac, para-aortic, splenic, hepatoduodenal, porta hepatis, and pancreaticoduodenal lymph nodes were included in all fields; splenic nodes were excluded if the kidney would be affected. Patients with tumors of the gastroesophageal junction also had treatment to paracardiac and paraesopha-geal nodes, but pancreaticoduodenal nodes were excluded. Radiation treatment plans were checked before initiation of EBRT to ensure standardization with 35% of the plans being modified to fit the radiation protocol.

FIGURE 1 Schema of Intergroup 0116 trial (INT 0116). Abbreviations: 5-FU, 5-fluorouracil; Gy, Gray; XRT, radiotherapy; N, number.

The median survival was 36 months in the treatment group and 27 months in the control group (p = 0.005). A benefit of adjuvant therapy was seen in the three-year OS rate (50% vs. 40%, p = 0.005) and the disease-free survival rate (48% vs. 31%, p = 0.001). Seventeen percent of patients had to stop therapy secondary to toxicities, and three patients died from complications related to their therapy. Although the study has been criticized for the fact that there was no standardization of surgical technique (only 9% had a full D2 resection), this represented the surgical practice in the institutions where the trials were performed. These data established the benefit of adjuvant combined modality therapy in resectable gastric cancer.

Following the report of INT 0116, a Korean group looked at the patterns of recurrence after a D2 resection and the INT 0116 postoperative regimen, accruing 322 patients into the prospective trial. Seven percent had local recurrence (the majority at the anastomosis), 12% had regional relapse, and 30% had distant failure. Recurrences were found in the original radiation field in 16%, accounting for 35% of all relapses (49). These locoregional failures compare favorably to those reported with surgery alone.

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